Natural product topical therapy in mitigating imiquimod-induced psoriasis-like skin inflammation-underscoring the anti-psoriatic potential of Nimbolide.

BACKGROUND: Psoriasis is a chronic inflammatory dermatological disorder having complex pathophysiology with autoimmune and genetic factors being the major players. Despite the availability of a gamut of therapeutic strategies, systemic toxicity, poor efficacy, and treatment tolerance due to genetic variability among patients remain the major challenges. This calls for effective intervention with the superior pharmacological profile. Nimbolide (NIM), a major limonoid is an active chemical constituent found in the leaves of the Indian Neem tree, Azadirachta indica. It has gained immense limelight in the past decades for the treatment of various diseases owing to its anti-proliferative, anti-inflammatory, and anti-cancer potentials. OBJECTIVE: The present study was centered around evaluating the anti-psoriatic effect of NIM in the experimental model of Imiquimod (IMQ)-induced psoriasis-like inflammation model. MATERIALS AND METHODS: Application of IMQ topically on the dorsum of Balb/c mice from day 0-6 prompted psoriasis-like inflammatory symptoms. Treatment groups included topical administration of NIM incorporated carbopol gel formulation and NIM free drug given through subcutaneous route. Protein expression studies such as immunohistochemistry, Western blotting, and ELISA were employed. RESULTS: It was clearly observed from our results that NIM significantly ameliorated the expression of inflammatory and proliferation mediators. Further, NIM in the treatment groups significantly improved classic Psoriasis Area Severity Index scoring when compared to IMQ administered group. CONCLUSION: It is noteworthy that NIM showed a predominant therapeutic effect as compared to other treatment group. To recapitulate, NIM has shown promising activity as an anti-psoriatic agent by remarkably ameliorating inflammation and associated proliferation.

Ferulic acid ameliorates the progression of pulmonary fibrosis via inhibition of TGF-ß/smad signalling.

Natural products are one of the best sources for the discovery of novel drugs and compounds for multiple diseases. Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, and fatal fibrotic disorder of lungs with unknown etiology and finite therapeutic choices. The use of naturally occurring phytomedicines has emerged to counteract many fibrotic disorders involving oxidative stress and inflammation. In the present study, we evaluated the protective effects of ferulic acid (FA), in an animal model of silica-induced PF. Pulmonary function of mice was evaluated by performing radiological analysis, bronchoalveolar lavage fluid (BALF), inflammatory cytokines, histology and protein expression studies. Our findings revealed that mice challenged with silica displayed characteristic features of pulmonary injury and fibrosis. However, treatment with FA significantly restored the accumulation of inflammatory cells in BALF. FA led to a partial reversal of silica-induced fibrotic changes in the pulmonary tissue. Subsequently, FA halts the progression of PF in a dose-dependent manner by ameliorating the expression of fibrotic proteins including collagen-I, TGF-ß, p-smad2/3 and prevented epithelial-mesenchymal transition (EMT). Collectively, the present study suggests that the inhibition of oxidative stress, inflammatory and TGF-ß/smad signalling might be involved in the observed anti-fibrotic benefits of FA against silica-induced PF in mice.

Honokiol: A polyphenol neolignan ameliorates pulmonary fibrosis by inhibiting TGF-ß/Smad signaling, matrix proteins and IL-6/CD44/STAT3 axis both in vitro and in vivo.

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-ß1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-ß/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-ß/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.

Inhalation of sustained release microparticles for the targeted treatment of respiratory diseases.

Delivering drugs through inhalation for systemic and local applications has been in practice since several decades to treat various diseases. In recent times, inhalation drug delivery is becoming one of the highly focused areas of research in the pharmaceutical industry. It is being considered as one of the major portals for delivering drugs because of its wide range of advantages like requirement of low concentrations of drug to reach therapeutic efficacy, surpassing first pass metabolism and a very low incidence of side effects as compared to conventional delivery of drugs. Owing to these favorable characteristics of pulmonary drug delivery, diverse pharmaceutical formulations like liposomes, nanoparticles, and microparticles are developed through consistent efforts for delivery drugs to lungs in suitable form. However, drug-loaded microparticles have displayed various advantages over the other pharmaceutical dosage forms which give a cutting edge over other inhalational drug delivery systems. Assuring results with respect to sustained release through inhalational delivery of drug-loaded microparticles from pre-clinical studies are anticipative of similar benefits in the clinical settings. This review centralizes partly on the advantages of inhalational microparticles over other inhalational dosage forms and largely on the therapeutic applications and future perspectives of inhalable microparticle drug delivery systems.

Therapeutic effects of Nimbolide, an autophagy regulator, in ameliorating pulmonary fibrosis through attenuation of TGF-ß1 driven epithelial-to-mesenchymal transition.

Pulmonary fibrosis is an irreversible lung disorder with predictable decline in lung function leading to respiratory insufficiency. Incidence of pulmonary fibrosis has been apparently increasing worldwide. Though aetiology of this disease remains unclear, potential roles of infection, disordered cell biology, genetic influence etc. have been proposed. Pirfenidone and nintedanib are the only two US FDA approved drugs to treat pulmonary fibrosis. Autophagy is a catabolic intracellular pathway that plays a crucial role in maintaining cellular homeostasis, which is involved in many disorders including fibrotic diseases. The present study investigated the role of Nimbolide, an important active constituent of Neem in TGF-ß1 induced in vitro and bleomycin induced in vivo model of pulmonary fibrosis, with a slight emphasis on regulation of fibrosis related autophagy. Protein expression studies showed significant reduction in mesenchymal, fibrotic markers and a substantial up regulation of epithelial markers upon treatment with Nimbolide. Nimbolide regulated autophagy signaling by dampening LC-3 and p-62 expression and increasing Beclin 1 expression as evidenced by immunohistochemistry and confocal microscopy. Our study demonstrates Nimbolide as a potent anti-fibrotic agent and its ability to regulate fibrosis associated autophagy.

Niclosamide alleviates pulmonary fibrosis in vitro and in vivo by attenuation of epithelial-to-mesenchymal transition, matrix proteins & Wnt/ß-catenin signaling: A drug repurposing study.

Drug repurposing off late has been emerging as an inspiring alternative approach to conventional, exhaustive and arduous process of drug discovery. It is a process of identifying new therapeutic values for a drug already established for the treatment of a certain condition. Our current study is aimed at repurposing the old anti-helimenthic drug Niclosamide as an anti-fibrotic drug against pulmonary fibrosis (PF). PF is most common lethal interstitial lung disease hallmarked by deposition of extracelluar matrix and scarring of lung. Heterogenous nature, untimely diagnosis and lack of appropriate treatment options make PF an inexorable lung disorder. Prevailing void in PF treatment and drug repositioning strategy of drugs kindled our interest to demonstrate the anti-fibrotic activity of Niclosamide. Our study is aimed at investigating the anti-fibrotic potential of Niclosamide in TGF-ß1 induced in vitro model of PF and 21-day model of Bleomycin induced PF in vivo respectively. Our study results showed that Niclosamide holds the potential to exert anti-fibrotic effect by hampering fibroblast migration, attenuating EMT, inhibiting fibrotic signaling and by regulating WNT/ß-catenin signaling as evident from protein expression studies. Our study findings can give new directions to development of Niclosamide as an anti-fibrotic agent for treatment of pulmonary fibrosis.

Nimbolide ameliorates fibrosis and inflammation in experimental murine model of bleomycin-induced scleroderma.

BACKGROUND: Clinical manifestations of skin fibrosis are very variable and ambiguous, making its management quite critical and challenging. The lack of appropriate established pharmacological interventions make its treatment even more complicated. Intricate details of the underlying pathogenesis are thus imperative to further explore different treatment possibilities. Of note, the TGF-ß/Smad signaling axis and epithelial to mesenchymal transition (EMT) are the principal offenders in this fibrotic disorder. OBJECTIVE: Our current study is aimed at demonstrating the antifibrotic and anti-inflammatory potential of nimbolide, a triterpene derived from Indian traditional plant neem, in a murine model of Bleomycin-induced scleroderma. METHODS: Male C57BL/6 mice were administered with Bleomycin injections subcutaneously, daily for 28 days, at a constant site on the dorsum of the mice. Treatment with nimbolide lasted from day 1 to day 28. At the time of study termination, the injected sites were collected and stored suitably to conduct further molecular experiments and protein expression studies. RESULTS AND CONCLUSION: The results of our study show that nimbolide can significantly intervene in the TGF-ß/Smad signaling axis and the consequent EMT process, thus attenuating deposition of extracellular matrix. Nimbolide also profoundly caused the regression of established inflammation-driven fibrosis, thus demonstrating both antifibrotic and anti-inflammatory activities. Another commendable finding of this study is that nimbolide was able to decrease the levels of LOXL2, a collagen cross-linker, which is aberrantly expressed in scleroderma. Although further mechanistic studies are required, our study displays nimbolide for the first time as a potent antifibrotic agent which can be used as a pharmacological intervention for the treatment of scleroderma.

Withaferin A attenuates bleomycin-induced scleroderma by targeting FoxO3a and NF-κß signaling: Connecting fibrosis and inflammation.

Scleroderma is an inflammatory autoimmune disease which begins with inflammation due to tissue injury and advances to progressive accumulation of extracellular matrix resulting in scarring and hardening of the skin. Inflammation is a salutary response to tissue injury caused by varied factors. While inflammation is required for systematic wound healing, dysregulated chronic inflammation often leads to tissue scarring. Prominent role of inflammation in pathology and physiology makes it a double edge sword. The objective of this study was to investigate the role of Withaferin A (WFA), a steroidal lactone from Withania somnifera in a 28-day murine model of bleomycin-induced experimental scleroderma. Withaferin A was administered at two doses 2 and 4 mg/kg intraperitoneally for 28 days. At the time of study termination, we observed significant reduction in dorsal skin thickness. Our results indicate that WFA was able to sufficiently suppress pro-inflammatory phase of fibrosis, TGF-ß/Smad signaling and also significantly repressed fibroblast conversion to myofibroblasts. Additionally, our study also demonstrated that WFA modulates FoxO3a-Akt-dependent NF-κß/IKK-mediated inflammatory cascade, which is a prime signaling pathway in fibrogenesis. The findings of this study are persuasive of WFA as an antifibrotic agent with promising therapeutic effects in scleroderma. © 2018 BioFactors, 44(6):507-517, 2018.